ATI-2173ATI-2173: A bridge to cure
Taking a bold first step toward a potential cure for people living with HBV
ATI-2173 is a next generation active site polymerase inhibitor (ASPIN) with improved pharmacokinetics (PK) relative to clevudine, and the same potent mechanism of action (MOA). Treatment with ATI-2173 results in sustained hepatitis B virus (HBV) DNA suppression off treatment, which is unique among approved nucleosides and investigational anti-HBV therapies.1
Combining ATI-2173 with a nucleoside analogue (NA), such as tenofovir (TDF) in a one-pill, once-a-day regimen could completely shut down HBV polymerase activity and viral replication, bringing patients with HBV closer to a cure2
In contrast to clevudine, ATI-2173 is ion-trapped in the liver as a monophosphate, leading to high liver triphosphate (the active metabolite) levels and low systemic clevudine exposure. Liver targeting has been confirmed in rat and monkey PK studies. Monkey PK studies confirmed 82% first-pass uptake.3
The only ASPIN in development leverages a unique mechanism to empower combination therapy1
ATI-2173 uses a novel MOA to inhibit viral replication
Chain-terminating NAs, like tenofovir and entecavir, compete for positions in the replicating viral DNA, expending themselves through incorporation to block some DNA synthesis through chain termination.4
ATI-2173 actively binds to and distorts the HBV polymerase enzyme’s active site to catastrophically disrupt all aspects of polymerase activity (protein priming, chain elongation, and DNA synthesis).1,5
- ATI-2173 is the only ASPIN in development
- ASPIN mechanism is complementary to all other approaches—potential to completely shut down viral replication and cure HBV2,6
- ATI-2173 alone or combined with TDF results in sustained HBV DNA suppression off treatment, unique among approved nucleosides and investigational anti-HBV therapies5
- Could prevent rapid off-treatment viral rebound and associated alanine aminotransferase flares1,5
ATI-2173—a descendant of clevudine
Clevudine, a first-generation ASPIN, was originally developed for the treatment of chronic HBV. In humans, monotherapy demonstrated equivalent antiviral efficacy to entecavir after 48 weeks. Its MOA uniquely demonstrated extended viral suppression following treatment discontinuation out to 24 weeks.7,8
However, clevudine was not liver targeted. It was voluntarily discontinued in phase 3 by its developer, Pharmasset, due to reversible proximal skeletal muscle myopathy, which emerged after a minimum of 8 months of dosing (median exposure 16 months, 1% of patients at 1 year). This adverse event was also observed in a 12-month clevudine monkey toxicology program with a dose and duration relationship.3
Aside from this rare adverse event, clevudine demonstrated a well-defined safety profile and efficacy data from 1500+ HBV-infected subjects. Further, combination treatment with adefovir demonstrated improved virological response with no viral resistance detected.9
Watch this video to discover how ATI-2173 disrupts cccDNA and serves as a powerful combination therapy asset in the treatment of HBV.
ASPIN vs nucleoside analogue (NA)
NA—Traditional, chain-terminating NAs inhibit some stages of DNA synthesis by competing for nucleotide positions in the HBV DNA chain, preventing priming and/or further elongation.4
ASPIN—Active metabolite is the only nucleotide that inhibits all stages of DNA synthesis by distorting its enzyme’s active site, noncompetitively.4
References: 1. Data on file. Antios Therapeutics, Doylestown, PA. 2. Mayers DL. ATI-2173: a novel active site polymerase inhibitor nucleotide (ASPIN). Presented at: Hep DART; December 5-9, 2021; Los Cabos, Mexico. 3. Painter GR, Trost LC, Blum MR, Szczech GM, Furman PA. Clevudine: a novel 1-β-L nucleoside analogue in clinical development for the treatment of HBV infection. In: Schinazi RF, Sommadossi J-P, Rice CM, eds. Frontiers in Viral Hepatitis. Elsevier BV; 2003:281-300. 4. Squires K, Ogilvie L, Huguet J, et al. Pharmacokinetics of ATI-2173, a novel active site polymerase inhibitor nucleotide (ASPIN), in a phase 1b clinical trial. Presented at: European Association for the Study of the Liver International Liver Congress; June 23-June 26, 2021. 5. Tomas M, Jucov A, Anastasiy I, et al. SAVE-1: phase 2a results of ATI-2173, a novel active site polymerase inhibitor nucleotide, combined with TDF in chronic hepatitis B patients. Presented at: Asian Pacific Association for the Study of the Liver Annual Meeting; March 30-April 3, 2022; Seoul, South Korea. 6. Squires KE, Mayers DL, Bluemling GR, et al. ATI-2173, a novel liver-targeted non-chain-terminating nucleotide for hepatitis B virus cure regimens. Antimicrob Agents Chemother. 2020;64(9):e00836-20. 7. Lee H-S, Chung Y-H, Lee KD, et al. A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2008;43(5):982-988. 8. Shin SR, Yoo BC, Choi MS, et al. A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B. Hepatol Int. 2011;5:664-670. 9. Tak WY, Yang JM, Kim BI, et al. A randomized, open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naïve chronic hepatitis B patients. Hepatol Int. 2014;8:375-381.